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A microRNA component of the p53 tumour suppressor network

Nature volume 447, pages 1130–1134 (2007)Cite this article

Abstract

A global decrease in microRNA (miRNA) levels is often observed in human cancers1,2, indicating that small RNAs may have an intrinsic function in tumour suppression. To identify miRNA components of tumour suppressor pathways, we compared miRNA expression profiles of wild-type and p53-deficient cells. Here we describe a family of miRNAs, miR-34a–c, whose expression reflected p53 status. Genes encoding miRNAs in the miR-34 family are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo. Ectopic expression of miR-34 induces cell cycle arrest in both primary and tumour-derived cell lines, which is consistent with the observed ability of miR-34 to downregulate a programme of genes promoting cell cycle progression. The p53 network suppresses tumour formation through the coordinated activation of multiple transcriptional targets, and miR-34 may act in concert with other effectors to inhibit inappropriate cell proliferation.

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Figure 1: Expression of miR-34 is correlated with p53 status in MEFs.
Figure 2: Genes encoding miR-34 are direct targets of p53.
Figure 3: miR-34 family miRNAs mediate growth arrest in a variety of cell types.
Figure 4: miR-34 regulates a programme of cell cycle and DNA damage response genes.

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Acknowledgements

We thank members of the Hannon and Lowe laboratories and the Rosetta Biology group for helpful input; M. Zhang and J. Burchard for bioinformatic analysis; J. Guo, C. Raymond and K. Niemeyer for miRNA quantification; J. Schelter and M. Kibukawa for cell cycle analyses and gene expression profiling; R. Diaz, M. Mehaffey, F. Huynh and the Rosetta Gene Expression Laboratory for technical assistance; and R. Dickins, J. Kurland, M. McCurrach, K. Diggins, A. Chicas, B. Stillman and B. Vogelstein for providing reagents and protocols. L.H. is a Fellow of the Helen Hay Whitney Foundation and is supported by a K99 grant from the NCI. S.W.L. and G.J.H. are supported by a program project grant from the NCI and are investigators of the Howard Hughes Medical Institute. This work was also supported in part by a gift from K. W. Davis.

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Author notes

  1. Elisa de Stanchina

    Present address: Present address: Memorial Sloan-Kettering Cancer Center, 415 East 68th Street, New York, New York 10021, USA.,

  2. Lin He and Xingyue He: These authors contributed equally to this work.

Authors and Affiliations

  1. Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA,

    Lin He, Xingyue He, Elisa de Stanchina, Zhenyu Xuan, Wen Xue, Lars Zender, Scott W. Lowe & Gregory J. Hannon

  2. Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA,

    Xingyue He

  3. Rosetta Inpharmatics, 401 Terry Avenue N., Seattle, Washington 98109, USA,

    Lee P. Lim, Jill Magnus, Aimee L. Jackson, Peter S. Linsley & Michele A. Cleary

  4. Advanced Research & Technology, Applied Biosystems, 850 Lincoln Centre Drive, Foster City, California 94404, USA,

    Yu Liang, Dana Ridzon & Caifu Chen

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Correspondence to Michele A. Cleary or Gregory J. Hannon.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S8, Supplementary Tables S1-S2, Supplementary Methods and additional references. (PDF 3172 kb)

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He, L., He, X., Lim, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007). https://doi.org/10.1038/nature05939

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